Extract

Abbreviations: AM = alveolar macrophages;
CS = cigarette smoke

Apoptosis
is a critical mechanism controlling cellularity in various tissues. It
is so far unknown whether apoptosis plays a role in cigarette
smoking-related pulmonary diseases. It is, however, reported that
inhaled toxic materials such as silica and particle matters induce
apoptosis of alveolar macrophages (AMs). This study was aimed to test
hypothesis that cigarette smoke (CS) may induce apoptosis of AMs. In
lung tissue specimens obtained from current smokers with pulmonary
emphysema, approximately 0.3% of the AM population were found to be
positive for terminal deoxynucleotidyl transferase-mediated nucleotide
nick end-labeling and immunostaining with monoclonal
anti-single-stranded DNA (ApoStain; Alexis Corp; San Diego, CA). In
in vitro studies, mouse, rat, and human AMs, and human blood
monocyte-derived macrophages cultured with aqueous cigarette smoke
extracts underwent apoptosis as evidenced by light and electron
microscopy, and terminal deoxynucleotidyl transferase-mediated
nucleotide nick end-labeling. This apoptosis was associated with
increased oxidative stress, Bax protein accumulation, mitochondrial
dysfunction, and mitochondrial cytochrome c release, but was
independent of p53, Fas, and caspase activation. The cigarette smoke
extract-induced apoptosis was inhibited by glutathione, ascorbic acid,
and α-tocopherol, which are antioxidants known to be present in
respiratory tract lining fluids. In in vivo studies where
rats were exposed to the smoke from 10 cigarettes over 5 h in an
exposure chamber, approximately 3% of AMs obtained by BAL showed
apoptosis after 24 h. To evaluate the role of lung antioxidants in
CS-induced AM apoptosis in vivo, glutathione-depleted rats
produced by administration of buthionine sulfoximine were exposed to
CS. There was a significant increase in CS-induced AM apoptosis in
glutathione-depleted rats compared with control rats. These results may
provide information to explain macrophage dysfunction and lung diseases
in cigarette
smokers.

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